Persistent but moderate hyperketonemia is common in newborn mammals, including man. Although ketone bodies are known to be a ready source of energy for developing extrahepatic tissues, their contribution to biosynthetic processes has not been fully determined. Recent evidence from our laboratory, as well as other, indicated that ketones can be incorporated into fatty acids and complex lipids in the brain of suckling rats and human fetuses. Since brain maturation includes a myelination process that relies on fatty acids, especially those with chains containing 22 and 24 carbons, and on the synthesis of sphingolipids and phosolipids, ketone bodies could contribute significantly to brain development. We therefore propose to assess the role of ketone bodies as precursors for the synthesis of cerebral lipids in developing rats. The fatty acid composition of various lipid classes synthesized from 14C-labeled ketones will be determined chromatographically and compared with that found in different regions of the brain from developing rats. The contribution of cytoplasmic acetoacetyl CoA synthetase versus ATP-citrate lyase pathways in generating acetyl CoA from ketones for lipogenesis will be evaluated by comparing the activities of these and other lipogenic enzymes during development, and by comparing the rate of lipogenesis from ketones in the presence or absence of (minus)-hydroxycitrate, a specific inhibitor of ATP-citrate lyase. We also intend to determine (1) whether acetyl CoA and malonyl CoA derived from ketones are utilized preferentially or equally for chain elongation and de novo synthesis of fatty acids, and (2) the effects of undernutrition and maternal diets on the synthesis of lipid from ketones in the brain of fetuses and suckling rats. Information obtained from this proposal will help clarify the mechanism and importance of lipogenesis from ketones. It may, in addition, suggest a means of stimulating this biosynthetic capacity to ensure an adequate supply of cerebral lipids for normal growth and development of the brain in human newborns, particularly undernourished, small-for-gestational age and premature infants.